The goal of this work is to clarify the initiation and development of the lipid-rich core region of the atherosclerotic fibrous plaque. Studies are performed with tissues from human aorta and sometimes coronary and other arteries, and with in vitro model systems. The work performed thus far has provided strong evidence for several new concepts, including the following: First, core formation is a very early event in the formation of some, and perhaps most, fibrous plaques. Second, cholesterol crystallization initially occurs in a setting of pre-existent intense extracellular lipid deposition. Third, although core formation deep in the intima is associated with the presence of foam cells in the superficial intima, early core lipid deposits do not result from foam cell necrosis. I hypothesize that a major portion of extracellular lipid deposits are assembled outside of cells from smaller lipid-rich particles, perhaps from lipoproteins, or perhaps from individual lipid molecules. Planned studies are designed to characterize this type of lipid deposition, elucidate its mechanism(s), and to determine possible effects of accumulated lipids on cells. Specific aims are: (1) To determine whether a progressive transformation of forms of lipid deposits may be seen in lesions of differing apparent age and to gain evidence for metabolism of lipid deposits, (2) to determine localization of apolipoproteins and other relevant antigens in lesioned and normal intima by immunoelectron microscopy, (3) to determine responses of arterial wall cells to potential toxic substances accumulated or generated with lipid deposits, and (4) to determine whether interaction between lipoproteins and arterial fibrous proteins can lead to sequestration of the lipoproteins. The importance of understanding development of the atherosclerotic core region is underscored by its role in causing plaque rupture or ulceration, leading to acute thrombotic or thromboembolic events.